Schizophrenia is an inherited, neuropsychiatric disorder characterized by episodes of psychosis and altered brain function. Despite previous research that successfully identified genetic variants associated with schizophrenia, scientists remain uncertain about which genes cause the condition and how their function is regulated.

The current study obtained blood samples from nearly 2,000 individuals in order to clarify which specific genes are actually affected by the genetic variants associated with schizophrenia and potentially provide a blueprint for researchers to undertake similar analyses for other complex diseases.

“We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1,714 individuals from three independent sample cohorts,” the authors wrote. “We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts—these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia.”

“This study highlights the power of integrating different types of genomic data to better understand how disease-associated DNA sequence variation actually influences the way in which genes function,” explained senior study author Jonathan Mill, Ph.D., professor of epigenetics at the University of Exeter Medical School. “Although our study focused on schizophrenia, we're now applying this approach to other types of complex disease.”

The team focused on both the underlying genetic sequence and DNA methylation—an epigenetic mark that regulates both gene expression and function. By profiling genetic and regulatory variation in the same samples, the group found that many of the genetic variants previously found to be associated with schizophrenia have potential effects on gene regulation.

Additionally, the research team identified epigenetic changes in 26 of 105 regions in the genome previously implicated in schizophrenia, prioritizing specific genes for further functional studies and as potential targets for novel treatments.

“It is clear that genetic studies need to look beyond simply sequencing DNA, and in this study we simultaneously profiled DNA methylation,” concluded lead study author Eilis Hannon, Ph.D., a bioinformatics research fellow in the Complex Disease Epigenetics Group at University of Exeter Medical School. “By aligning the results from these two molecular approaches, we have generated a list of genes directly affected by schizophrenia genetic risk factors.”